The translational potential of α-tocopheryl succinate (a.k.a., vitamin E succinate; VES) in cancer therapy has been the focus of many recent investigations in light of its efficacy in suppressing tumor cell proliferation without incurring toxicity to normal cells. See for example Wang et al., Mol. Nutr. Food Res., 50, 675-85 (2006). Substantial evidence indicates that VES exhibits a unique ability to target multiple signaling pathways associated with carcinogenesis, tumor progression, and metastasis, including those mediated by NF-κB, PKCα, sphingolipids, Bcl-2/Bcl-xL, androgen receptor (AR), vascular endothelial growth factor (VEGF), and insulin-like growth factor binding protein-3. Although some of these signaling targets might be cancer type-specific, this broad spectrum of action in conjunction with low toxicity underlies the therapeutic value of developing VES into useful agents for cancer treatment or prevention.
One of the cancers affected by VES is prostate cancer. A significant challenge in the management of patients with prostate cancer is the treatment of hormone-refractory prostate cancer (HRPC), a hallmark of incurable and lethal prostate cancer progression. To date, chemotherapeutic regimens provide substantive benefits through palliation, but yield no definitive enhancement in survival. A clear need exists for novel strategies that will improve the treatment of prostate cancer and ultimately increase the survival of prostate cancer patients. Accordingly, significant efforts have been expended to identify small-molecule agents targeting dysregulated pathways associated with HRPC.
The Ras signaling system provides a potential target for small molecule agents being developed for use against prostate cancer. The proto-oncogenic Ras functions as a molecular switch for signal transduction pathways controlling cell growth and differentiation, including those mediated by Akt, ERKs, RalA GTPase, and the transcription factor c-Myc. As these tumorigenic effectors of Ras regulate various aspects of oncogenesis in different cellular contexts, evidence indicates that Ras signaling represents a major driving force for prostate cancer progression to an androgen-independent state. Weber et al., J. Cell Biochem, 91, p. 13-25 (2004). Moreover, dominant negative inhibition of endogenous Ras activity has been shown to restore androgen sensitivity to hormone-refractory C4-2 prostate cancer cells. Bakin et al., Cancer Res., 63, p. 1975-80 (2003). Together, these finding indicate that Ras signaling represents a therapeutically relevant target for HRPC treatment.
Farnesyltransferase (FTase) inhibitors were originally developed as anti-Ras compounds and novel target-based drugs for cancer treatment. However, R115777, a potent FTase inhibitor, showed little anti-tumor activity in minimally pretreated patients with androgen-independent prostate cancer. This lack of clinical efficacy underlies uncertainty over whether Ras is a relevant target of FTase inhibitors in humans.
PP2A is a tumor suppressor that antagonizes Ras signaling. PP2A is a ubiquitously expressed protein serine/threonine phosphatase that accounts for a large fraction of phosphatase activity in human cells. Janssens et al., Biochem J., 353, p. 417-39 (2001). PP2A is composed of a dimeric core enzyme that includes a 65-kDa scaffolding A subunit (Aα or Aβ), a 36-kDa catalytic C subunit, and variable regulatory B subunits. The C subunit of PP2A undergoes reversible methylation on its C terminus, which regulates the binding of B regulatory subunits and PP2A phosphatase activity. Different B subunits confer different properties of PP2A in dephosphorylating downstream substrates, by which PP2A mediates distinct cellular functions. Substantial evidence indicates that PP2A functions as a tumor suppressor through its ability to mediate the dephosphorylation and inactivation of a number of tumorigenic proteins, including Akt, ERKs, and RalA. Mumby M., Cell, 130, p. 21-4 (2007). The fact that all of these tumorigenic PP2A substrates are downstream targets of Ras suggests that a major tumor suppressive activity of PP2A is to antagonize Ras signaling. Thus, from a therapeutic perspective, developing small-molecule activators of PP2A activity represents a potentially effective strategy to counter Ras signaling and thereby re-sensitize prostate cancer cells to androgen ablation.